Inheritance patterns of HLA and T cell receptor (TCRalpha and TCRbeta) genes which are known to play important roles in a variety of immune processes have been analyzed in human families. The extent of the TCR repertoire was investigated by analysis of TCR alpha and beta specific cDNA libraries prepared from RNA samples derived from PHA-stimulated peripheral T lymphocytes using a technique involving the Polymerase Chain Reaction (PCR). Clones were obtained that correspond to 21 different TCRbeta and 25 different TCRalpha variable (V) gene families including 4 Vbeta and 6 Valpha families that have not been described previously. Genetic variation in TCR genes was examined by (i) Southern blot analysis of both conventional and pulsed field gels (PFG) using specific DNA probes to identify restriction fragment length polymorphisms (RFLP); (ii) non-denaturing acrylamide gel electrophoresis to identify single stranded conformational polymorphisms (SSCP) and, (iii) direct sequence comparisons of TCR V region genes. All techniques reveal limited polymorphism in TCR gene segments. A single nucleotide substitution identified in the Vbeta1 gene resulted in an amino acid substitution located within a hypervariable region, whereas single nucleotide substitutions in both Vbeta12 and Valpha22 genes were found to be conservative. In contrast to the limited polymorphism observed with individual gene segments, TCR haplotypes are highly polymorphic. There is considerable polymorphism in the combination of markers inherited together in both TCRalpha and TCRbeta haplotypes. In addition, variability in TCR gene complexes derives from the insertion or deletion of segments of DNA; two frequently occurring insertion/deletion related polymorphisms were found in the TCRbeta complex. The locations of the IDRP were determined by the development of an extended map of the TCRbeta complex showing that one involved a stretch of about 30 kb in the V region and another spans about 15kb near the C region. Analysis of 40 sibling pairs concordant for the relapsing-remitting form of Multiple Sclerosis (MS) revealed that a gene within the TCRbeta complex or a closely linked locus influences susceptibility to MS.